Twin Research and Human Genetics

C-Reactive Protein (hs-CRP) is a common marker for human inflammation, a response to perceived threat and precipitate to many compromising health conditions. Previous work demonstrated that in addition to other biological features that may be predictive and explanatory of variance in inflammation, psychosocial influences may play a role. The present work uses structural equation modeling to examine pathways including socioeconomic status (SES), psychological capital (PsyCap), and perceived discrimination (Discrim) -insofar as they explain variance in hs-CRP, potentially moderated by neurological lateralization (handedness). Body mass index (BMI), an indicator of body composition, stood as the strongest predictor of the obesity-related inflammatory marker (ORIM). On average, females are predicted to have higher hs- CRP scores than males. The psychosocial constructs were estimated to have little to no effect on inflammation (via hs-CRP) in the analysis sample (ADD Health Study) in either group (left and right-handers) although a small, statistically non-zero indirect path is found in the retained model for right-handed participants (given statistical power for estimation). With this finding, contextual effect estimates are provided with regard to the effect of perceived discrimination on hs-CRP given the range of SES and BMI.

Importance: In adolescence, attempts to lose weight are common, but their long-term impacts on mental and physical health are not known. Objective: To investigate the association between adolescent dieting and exercising to lose weight and adult trajectories of depressive symptoms and body mass index (BMI). Design: A longitudinal cohort study of children born between April 5 and 11, 1970, and followed up to age 51 years. Setting: Adolescents in the 1970 British Cohort Study in England, Wales and Scotland. Participants: A total of 4,650 adolescents with available exposure data. Exposures: Self-reported lifetime dieting or exercising for weight loss measured at age 16 years. Main Outcomes and Measures: Depressive symptoms measured with the nine-item Malaise Inventory, and BMI derived from self-reported height and weight, at ages 26, 30, 34, 42, 46, and 51 years. Results: Among 4,650 adolescents (56.7% girls, 97.7% White), 1,938 (41.7%) had dieted and 343 (7.4%) had exercised for weight loss by age 16 years. In fully adjusted analyses controlling for a wide range of child- and family-based confounders including prior BMI and emotional difficulties, there was evidence that adolescents who had dieted had higher adult depressive symptom trajectories (adjusted mean difference [aMD] 0.13, 95% CI 0.03-0.24, p=0.015) and higher and increasing adult BMI trajectories than those who had not dieted. There was also evidence that adolescents who exercised for weight loss had higher adult depressive symptom (aMD 0.18, 95% CI 0.02-0.34, p=0.031), and BMI trajectories (aMD 0.37, 95% CI -0.03, 0.78, p=0.071), though evidence of the latter was weak. Conclusions and Relevance: Behaviours aimed at weight loss occurring in adolescence might be a shared risk factor for depressive symptoms and high BMI in adulthood. If causal, these findings could suggest that reducing pressures to lose weight in adolescence may help prevent poor mental and physical health across the lifecourse.

Early-life exposures are important to several late-life health outcomes. We sought to study the effect of an in utero nutritional environment and its interaction with Alzheimer's disease (AD) genetic risk on late-life cognitive function. We used a natural experiment created by the pellagra epidemic, a nutritional disease caused by a vitamin B3 deficiency, to evaluate the association between in utero pellagra epidemic exposure and late-life cognitive function in the Health and Retirement Study (N = 18,285). We also evaluated whether the in utero exposure could modify the AD polygenic score's (PGS) effect on cognition. In utero pellagra epidemic exposure was significantly associated with cognition ({beta} = -0.025). However, these effects were not isolated to the prenatal period as exposure during childhood periods also had an effect. The interaction between the in utero exposure and the AD PGS was significant, where the genetic effect on cognition was amplified with increasing (progressively worse) in utero exposure levels. These associations imply that the early-life nutritional environment affects late-life cognitive function and that these effects can modify genetic risk.

Background: Depression and anxiety symptoms emerge early in life. We examined developmental trajectories of emotional symptoms, starting from early childhood, in three UK birth-cohorts spanning successive generations and diverse socio-ethnic contexts. Methods: Using data from three longitudinal, population-based UK birth-cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Millenium Cohort Study (MCS), and Born in Bradford (BiB) we identified group-based trajectories of emotional symptoms using repeated Strengths and Difficulties Questionnaire, Emotional Subscale (SDQ-E) scores from ages 3-14y. Baseline samples comprised children with [≥]1 SDQ-E measure between age 3-14y (NALSPAC=11,025; NMCS=15,446; NBiB=6711). Participants were born three decades apart (ALSPAC: 1990-2, MCS: 2000-2, BiB: 2007-10) in distinct socioeconomic and ethnic contexts. We characterised group membership by: female sex, non-white ethnicity, maternal depression/anxiety and IMD quintile. In ALSPAC we modelled associations between trajectories and depression/anxiety diagnoses in early adulthood (24y and 30y). Results: In all cohorts 49% were female. ALSPAC had few non-white participants (4%) compared to MCS (17%) and BiB (66%). Each cohort had low-, mid- and high-level symptom trajectories. High-level trajectories comprised 6-7% of the population in each cohort. However, in younger cohorts, high-level symptom trajectories started high and persisted from age 3-5y but started low and increased in the oldest cohort. Female sex and maternal depression/anxiety were associated with higher odds of high-level or increasing symptom trajectories across all cohorts. Higher socioeconomic status and belonging to the ethnic majority was protective. Mid- and high-level symptom trajectories had higher odds of depression/anxiety diagnoses in early-adulthood in the older ALSPAC cohort. Conclusions: Developmental trajectories of emotional symptoms across childhood and adolescence are broadly similar across generations and diverse social contexts. However, children born more recently and in more diverse contexts may experience more persistent, severe emotional symptoms from a young age Key words: Longitudinal trajectories; emotional symptoms; SDQ, ALSPAC; MCS; Born in Bradford

Autism development involves multiple genetic and early-life environmental factors. Studying the placenta's gene expression profile may reveal key mechanistic pathways in autism development. Here, using a nested case-cohort design within an Australian population-derived prebirth cohort study (n=1074), we identified 1,644 differentially expressed genes (DEGs; FDR<0.05) in the placenta of children with autism diagnosis (n=43), compared to those without (n=120). The top enriched pathways related to mitochondrial translation, oxidative stress, RNA processing and transcription regulation. CYP1A1, the most important xenobiotic-metabolising enzyme of the placenta, was the top downregulated DEG in the placenta of children with autism, while immuno-regulatory human leukocyte antigen (HLA)-related genes were among the top upregulated DEGs. A machine learning-based approach predicted autism from the transcriptomic data with a median sensitivity of 0.57 (2.5th-97.5th centiles: 0.29, 0.76) and median specificity of 0.92 (2.5th-97.5th centiles: 0.78, 0.98). Weighted Gene Correlation Network Analysis identified eight affected placental gene modules, with the largest five modules being enriched primarily for mitochondrial bioenergetics, oxidative phosphorylation and RNA processing pathways. This placental transcriptomic signature of impaired mitochondrial function and gene transcription regulation among infants subsequently diagnosed with autism has profound implications for understanding both risk factors and prediction, suggesting the possibility of identifying modifiable prenatal pathways to improve autism outcomes.

Background Literature investigating mediation of the association between child abuse and dementia has largely considered composite adverse childhood experience scores rather than individual adverse experiences, despite evidence that different experiences have different impacts on dementia risk. Additionally, prior studies consider mediators in isolation, despite known associations between mediators which may impact indirect pathways from child abuse to dementia. Objectives To investigate whether potentially modifiable health and lifestyle factors mediate the association between child abuse and dementia. Methods We used data from the English Longitudinal Study of Ageing to investigate associations between child abuse and dementia (N:5,448). Indirect pathways through four mediator categories (education, health behaviours, mental health and cardiovascular health) were examined. We used regression modelling to estimate associations between child abuse, mediators and dementia, and causal mediation analysis using the g-formula to estimate the joint indirect effect through the mediators. Results Individuals who experienced child abuse had, on average, an 80% higher hazard of dementia, compared to those who did not (RTE HR:1.80, 95% CI:1.21-2.39). Mental health mediators showed strong associations with both child abuse and dementia. Evidence for other mediators was weaker. Education, health behaviours, mental health and cardiovascular health mediated approximately 18% of the association. Sensitivity analysis revealed that almost all this mediation occurred through mental health. Conclusions Child abuse was associated with higher risk of dementia. Joint mediation analysis suggested that education, health behaviours, cardiovascular health, and mental health accounted for a relatively small proportion of the observed association, with most mediation occurring through mental health. Future research must focus on other potential pathways from child abuse to dementia, including biological and social mechanisms.

Disordered eating attitudes exist on a continuum that extends well below clinical diagnostic thresholds, yet the cognitive correlates of this non-clinical variation remain incompletely understood. Previous research linking executive functioning to disordered eating in non-clinical samples has relied almost exclusively on self-report questionnaire measures of executive function, which show weak correspondence with performance-based assessments. This methodological reliance leaves open the question of how objective executive performance relates to eating behavior across the spectrum. The present study addressed this gap by examining the association between performance-based measures of executive function and disordered eating attitudes in a non-clinical sample of 243 university students via an online experiment, using a dimensional approach consistent with the Research Domain Criteria framework. Participants completed established neurocognitive tasks covering three executive function domains: working memory was assessed with Digit Span and an N-back task, inhibitory control with a Go/No-Go task, and cognitive flexibility with the Card Sorting Task. Disordered eating attitudes were indexed using the EAT-26 total score and its subscales. A notable correlation was identified between cognitive flexibility and disordered eating attitudes, while working memory and inhibitory control exhibited no such association. Overall, our findings provide evidence for associations between executive functioning and disordered eating attitudes in a non-clinical sample.

Background: Unintended pregnancies can introduce stress and shift life trajectories. Social support may buffer these effects, yet its influence during an unintended pregnancy and into the early parenthood period is not clear. This study aimed to understand the types and gaps of social support experienced throughout this period. Methods: This study utilized interview data under the RISE UP study in The Hague, the Netherlands. 13 mothers and 8 partners who experienced an unintended pregnancy participated in semi structured interviews between 2024 and 2025. Interviews were thematically analyzed using House's social support framework. Results: Different types of support were highlighted across the entire timeline from pregnancy to early parenthood, underlining its dynamic nature. Emotional and instrumental support stood out the most throughout. A key form of emotional support was knowing that support is available, even if not needed immediately. Conclusions: Perceived support during unintended pregnancy is shaped more by contextual factors than by pregnancy intention. While emotional and instrumental support are valued throughout, their form differs by the family's unique circumstances, emphasizing the need for tailored support across the perinatal and postpartum periods.

Background and Objective: Diabetes mellitus (DM) causes autonomic neuropathy, which may alter nocturnal respiratory rate (NRR). To test the association between DM and NRR, we analyzed elective polysomnograms of four large observational cohorts. Research Design and Methods: We performed cross-sectional analysis of over 25,000 individuals with polysomnograms (PSGs) from the Sleep Heart Health Study (SHHS), Hispanic Community Health Study/Study of Latinos (HCHS/SOL), Osteoporotic Fractures in Men Study (MrOS), and Wisconsin Sleep Cohort (WSC). Patient-level NRRs were derived from inductance plethysmography waveforms. DM status was determined by self-report, physician diagnosis, medication use, or laboratory values, depending on the cohort. We related DM and NRR (continuous and dichotomized) using logistic regression models and adjusted for potential confounders. Cohort-specific results were combined using random-effects meta-analysis. Results: Meta-analysis of unadjusted models showed a pooled odds ratio (OR) of 1.10 (95% CI:1.04-1.17) for each breath-per-minute (brpm) increase in NRR. This association remained significant after multivariable adjustment (OR:1.06, 95% CI:1.02-1.11). Dichotomized analyses similarly showed higher odds of DM across dichotomization thresholds ranging from 15 to 21 brpm. At a threshold of 18 brpm, the unadjusted pooled OR was 1.77 (95% CI:1.23-2.55, P=0.0022), and the adjusted OR was 1.49 (95% CI:1.10-2.02, P=0.0098). Conclusions: Clinically stable outpatients with elevated NRR have an increased prevalence of DM. Additional studies are needed to investigate whether the mechanism is autonomic neuropathy and whether monitoring NRR can detect early complications of DM.

Objective: Studies assessing the validity of screening measures for avoidant/restrictive food intake disorder (ARFID) remain scarce. We evaluated the diagnostic performance and validity of an online, parent-reported screening approach for ARFID in a population-based sample of children. Methods: Participants were drawn from the ARFID Initiative Sweden (ARIES) cohort and included 65 children aged 6-14 years. Parents completed three screening questionnaires (Pica, ARFID, and Rumination Disorder Interview-ARFID Questionnaire [PARDI-AR-Q], Nine-Item ARFID Screen [NIAS], and Parent Eating Disorder Examination Questionnaire [PEDE-Q]), followed by a diagnostic interview (PARDI). Diagnostic performance indices (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) were calculated. Convergent validity was assessed via correlations between questionnaire and interview dimensions. Results: The combined screening algorithm demonstrated perfect sensitivity and NPV, indicating accurate detection of all ARFID cases and exclusion of non-cases. Specificity was high (0.83), and PPVs ranged from 0.91 to 0.95, decreasing to 0.78 under a more conservative operationalization of ARFID Criterion A4 (psychosocial impairment). Diagnostic performance varied across ARFID criteria: PPVs were low for medically anchored Criteria A1-A3 but high for Criterion A4 (psychosocial impairment; PPV=0.95). Correlations between screening measures and corresponding interview dimensions were generally moderate to strong, supporting convergent validity. Children meeting threshold ARFID criteria showed significantly greater symptom severity than subthreshold cases at screening. Discussion: These findings support the use of a multi-instrument, parent-reported screening approach for ARFID in large-scale pediatric research and highlight the centrality of psychosocial impairment, underscoring the need for standardized operationalization of this criterion.

Objective: This systematic review and meta-analysis examined 1) the effects of stress management interventions on changes in stress eating for women, and 2) the longevity of these effects, by summarizing and assessing evidence from controlled and non-equivalent pretest-posttest intervention studies. Method: Five databases (PsycINFO, PubMed, Medline, Web of Science, CINAHL), existing sources, and grey literature were searched (February - June 2025). Studies that assessed stress eating or emotional eating, included a stress management intervention, and comprised at least 70% women were included. The primary outcome was reduction in stress eating. Data were pooled in meta-analyses using multi-level random-effects models and subset by follow-up period. Risk of bias was assessed via funnel plots and sensitivity analyses. Results: Sixty studies with 119 effect size estimates were included in the primary analysis. Pooled estimates indicated that stress management interventions significantly reduced stress eating (Hedges g = -0.4174, p < 0.001), with pre-post designs having larger effects than controlled trials. Subgroup analyses of follow-up periods found small effects in the short-term (before 3 months; Hedges g = -0.4202, p < 0.0001) and moderate effects for mid-term (3-6 months; Hedges g = -0.5886, p < 0.0001). Effects beyond 6 months were small and nonsignificant (Hedges g = -0.4370, p = 0.0660). Conclusion and Relevance: Stress management interventions appear to be effective for reducing stress eating for women, suggesting the potential to incorporate stress management in interventions targeting obesity. Effects may be only sustained 6 months post-intervention, suggesting the need for strategies to bolster long-term effectiveness.

Background: Documentation burden significantly impacts nursing workload and well-being, with nurses spending an estimated 20-40% of their time on documentation. Ambient AI technologies offer potential to reduce documentation time by mapping real-time nurse-patient conversations to structured EHR data entries with human-in-the-loop verification. Methods: This protocol describes a pragmatic, EHR-embedded randomized controlled trial evaluating the effectiveness of an Ambient AI tool in reducing nursing documentation time across three inpatient medical/surgical units. The study employs a closed-cohort, stepped-wedge, unit-randomized design, integrating the intervention into routine clinical workflows. The primary outcome is documentation time per shift hour, derived from EHR audit logs. Secondary outcomes include documentation burden, professional well-being, and perceived usability. Results: The trial is being implemented within a shared governance model that integrates executive oversight, operational feasibility, and research rigor. Multidisciplinary workgroups coordinate technical integration, user experience, and analytics, ensuring alignment between operational priorities and pragmatic trial objectives. Early implementation has highlighted the importance of adapting training and analytic strategies to address differential intervention exposure, as well as the need for rapid operational responses to late-emerging technical issues. Discussion: This protocol demonstrates the feasibility of embedding a randomized pragmatic trial within a health system-led operational deployment of Ambient AI for inpatient nursing documentation. The approach highlights the necessity of adapting existing outpatient provider-focused AI implementation strategies for inpatient nursing, emphasizing the unique nature of different nursing care environments. Recruitment challenges and the integration of research with operational workflows are discussed as key considerations for future pragmatic AI trials in nursing. Keywords: Artificial Intelligence; Ambient AI; Nursing Documentation; Documentation Burden; Large Language Models; Speech Recognition Software; Stepped-Wedge Design ClinicalTrials.gov Identifier NCT07456241V4: 2026-05-27 https://clinicaltrials.gov/study/NCT07456241

Background: As global obesity rates have increased, so too have efforts to manage obesity. This work estimates how many people maintain a lifelong healthy weight, have weight loss potential, and who successfully lose weight without medical support. Methods: Using the 1946 National Survey of Health and Development (1946NSHD; n=4,423), the 1958 National Child Development Study (1958NCDS, n=16,749) and the 1970 British Cohort Study (1970BCS; n=15,612), we quantify the prevalence of lifetime healthy weight, overweight and obesity by ages 51-55, and compare prevalence in early adulthood to the 2000-02 Millenium Cohort Study (2001MCS; n=9,675). We identified those who maintained, lost, gained, or cycled weight up to ages 50-55 (1958NCDS) and 46-54 (1970BCS), relative to their highest body mass index (BMI) before age 42, and examined predictors of group membership using multinomial regression models. Findings: In 1970BCS one-in-five people maintained a healthy BMI into their fifties, whilst 43% experienced obesity at least once, up from 25% in 1946NSHD. In 2001MCS 19% already had obesity by age 23, compared to 1-2% in the oldest cohorts. Across cohorts, those who maintained a healthy BMI were more socioeconomically advantaged, while those who experienced obesity were the most disadvantaged. Among those with obesity, a similar proportion lost weight in both cohorts (~13%), whilst 33-39% continued weight gain. Few potential drivers were associated with weight loss after adjusting for peak BMI, whilst socioeconomic disadvantage predicted further weight gain, as did the intention to lose weight. Interpretation: Weight loss from obesity is rare and the rate has remained consistent over time, whilst weight gain into obesity is common, and prevalence of lifetime obesity has increased.

Background: Deaf and hard of hearing (HoH) experienced complex challenges during the COVID19 pandemic, including obscured visual communication from mask mandates, inaccessible public health messaging, and inadequate interpreter availability. We examined whether hearing status predicted nonmedical COVID19 impact on a global level. Methods: We conducted a nested cross-sectional analysis within a global study collecting data across two waves (April to May 2020 and July to August 2022) from 184 countries. Participants (N=7,998) were categorized as Deaf (n=304), Hard of Hearing (HoH; n=951), or Hearing (n=6,743). The primary outcome was a composite COVID-related non-medical Personal Impact TScore derived from 14 items across employment, resource access, and healthcare domains. Multinomial logistic regression models progressively adjusted for demographic, structural, and psychosocial variables. Results: Deaf participants reported substantially higher rates of pandemic-related job loss (28.9% vs. 9.6% hearing), healthcare cancellations (39.9% vs. 24.6%), and inability to obtain basic supplies. Over half (55.9%) of Deaf participants scored above the median composite impact index, compared to 39.2% of hearing participants. In the fully adjusted model, Deaf status remained an independent predictor of high non-medical impact (aOR=1.6, 95% CI: 1.1 to 2.4). HoH status showed no statistically significant difference from hearing participants in any model. Conclusions: People identifying as Deaf experienced significant disparities during COVID19 when compared with HoH or hearing people, driven by language access barriers and institutional exclusion rather than hearing loss per se. These experiences underscore the importance for systemic interventions centering on accessible communication, Deaf-centered needs, and reducing audism in Deaf-hearing interaction.

Abstract Background: The influence of taurine on biological ageing remains unclear, particularly whether it acts as a causal driver or a functional biomarker. We aimed to disentangle the distinct roles of plasma taurine relative abundance, dietary taurine supply, and genetic metabolic capacity on all-cause mortality and unhealthy ageing. Methods: This prospective study used data from the Korean Genome and Epidemiology Study (2001~2022). A subcohort of 2,321 participants (mean age 56.5 years; 51.4% female) with complete metabolomic, dietary, and genomic data was analyzed. Three independent pathways were evaluated: (1) plasma taurine/total amino acid (AA) ratio, (2) dietary taurine to protein ratio, and (3) a weighted genetic risk score (GRS) from 21 SNPs in taurine biosynthesis and transport genes. Primary outcomes were all-cause mortality and unhealthy ageing (Physiological Healthy Ageing Index [PHAI] score [&le;] 25th percentile). Results: A higher plasma taurine/total AA ratio was consistently associated with improved ageing outcomes. Participants in the highest quartile showed 29% lower all-cause mortality (Hazard Ratio [HR], 0.71; 95% Confidence Interval [CI], 0.52-0.98; P for trend = .04) and lower risk of PHAI-based unhealthy ageing (HR, 0.77; 95% CI, 0.59-1.00; P for trend = .04) versus the lowest quartile. Dietary taurine-to-protein ratio was not associated with mortality (P for trend = .70), nor was the GRS (P for trend = .74). Conclusions: The protective association of taurine was linked to its relative abundance within the systemic amino acid pool, rather than dietary intake or genetic predisposition, supporting taurine as a functional biomarker of metabolic efficiency rather than a deterministic causal driver of ageing.

Obesity is associated with low-grade inflammation, which - our prior work shows - causally and reversibly increases effort aversion and related brain responses during food-related decision-making. However, how these laboratory findings translate to daily-life (food) motivation remains unclear. This study investigated low-grade inflammation in more ecologically valid measures of (food-related) motivation in obesity. We conducted a cross-sectional study (N=145 women, BMI>27 kg/m2, 18-59 yrs) and a 12-week randomized controlled trial (N=57 women, BMI>30 kg/m2, 18-59 years, C-reactive protein (CPR)>3 mg/l) testing the anti-inflammatory drug colchicine versus placebo. We measured effort-related food intake using a bogus taste test, daily-life motivation using ecological momentary assessment (EMA), and dietary intake using a food frequency questionnaire (FFQ). INFLA-score (CRP, white blood cell count, neutrophil-to-lymphocyte ratio, platelets) related to lower intake of high-effort food items on the taste test ({beta} -0.26 SD, p=0.011), lower engagement in high-effort activities (OR 0.72, p<0.001), and negatively moderated the association between anticipation and activity completion in EMA (OR 0.89, p=0.032). On the FFQ, INFLA-score related to lower intake of legumes and fruits and more intake of processed meat (all p<0.05). Colchicine decreased overall caloric intake ({beta} -341 kcal, p=0.018). A decrease in inflammation related to healthier dietary choices (Spearman {rho}=0.37, p=0.013). Colchicine did not affect effort-related food intake on the taste test or EMA. These findings indicate that that obesity-related inflammation is associated with increased effort-related food intake and motivation in daily life, and that reducing inflammation decreases (unhealthy) food intake. Such effects may partly underlie the challenges of achieving and maintaining weight loss.

Young adults frequently report cognitive complaints often attributed to sleep loss alone. However, subjective cognitive functioning is shaped by broader lifestyle and affective factors. Cross-sectional data were analyzed from 530 young adults (mean age 22.1 +/- 2.3 years) to examine the independent, interactive, and cumulative associations of short sleep duration, low physical activity, and psychological distress with everyday cognitive failures. Cognitive failures were strongly associated with sleep duration, physical activity, sleep quality, and distress in univariate analyses. However, hierarchical regression revealed that psychological distress, poor sleep quality, and short sleep duration were the dominant independent correlates of cognitive failures, collectively explaining a substantial proportion of variance in Cognitive Failures Questionnaire scores (R-squared = 0.585, p < 0.001). In contrast, the apparent protective effect of physical activity was not observed after adjustment for sleep and distress (p = 0.976), and no significant sleep-by-physical activity interaction was observed. Further, cumulative risk modeling demonstrated a robust dose-dependent relationship, with cognitive failures increasing progressively as behavioral and psychological risk factors accumulated (p < 0.001). Individuals exposed to all three risk factors exhibited more than double the cognitive failure burden observed in individuals with no risk factors. These results indicate that the cognitive burden in young adults can best be described by an additive increase of behavioral and psychological risk factors as a function of the co-occurrence, rather than by the presence of compensatory effects of lifestyle risk factors. Interventions aimed at preserving cognitive function may therefore benefit from simultaneously targeting sleep health and psychological well-being rather than relying on physical activity alone to offset cognitive burden.

ABSTRACT IMPORTANCE Childhood obesity is a growing global health concern associated with adverse physical, psychiatric, and neurodevelopmental outcomes. Although previous neuroimaging studies have linked obesity to widespread alterations in brain structure and function, it remains unclear how well multimodal neuroimaging measures and genetic markers can predict future weight gain and inform early intervention strategies. OBJECTIVE To evaluate the predictive utility of multimodal MRI measures and polygenic risk scores for obesity in estimating proportional body weight at baseline and predicting weight gain over one year in preadolescent children. DESIGN, SETTING, AND PARTICIPANTS This study used data from the Adolescent Brain Cognitive Development (ABCD) Study, a large-scale, multisite longitudinal cohort of children aged 9 to 10 years (N = 11,880). Analyses included baseline data collected between 2016 and 2018, and one-year follow-up data collected between 2018 and 2020 across multiple imaging sites. MAIN OUTCOMES AND MEASURES Elastic net regression models were applied to structural MRI (including diffusion tensor imaging) and resting-state functional MRI data to predict baseline triponderal mass index (TMI), a weight-for-height measure that more accurately reflects adiposity in children than body-mass index (BMI). Longitudinal classification models were developed to predict excess weight gain relative to normative developmental trajectories at one-year follow-up. Models were evaluated with and without the inclusion of polygenic risk scores and other non-imaging covariates. Generalizability was assessed using leave-one-site-out cross-validation. RESULTS Structural MRI measures predicted baseline TMI with an R^2 of 0.21, whereas resting-state functional MRI measures predicted TMI with an R^2 of 0.08. Classification models predicted one-year weight gain with area under the receiver operating characteristic curve (AUC) values of 0.73 for structural MRI and 0.60 for resting-state functional MRI. Including polygenic risk scores and other covariates improved model performance (structural MRI: R^2 = 0.25, AUC = 0.75; resting-state functional MRI: R^2 = 0.15, AUC = 0.69). Leave-one-site-out cross-validation revealed reduced generalizability across imaging sites (structural MRI R^2 = 0.13-0.17; resting-state functional MRI R^2 = 0.02-0.09; structural MRI AUC = 0.73-0.74; resting-state functional MRI AUC = 0.60-0.67). CONCLUSIONS AND RELEVANCE Multimodal MRI measures were associated with proportional body weight and demonstrated modest predictive utility for future weight gain in preadolescent children, explaining up to one fifth of the variance in weight-related outcomes. The addition of genetic and non-imaging variables improved prediction accuracy, underscoring the multifactorial nature of childhood obesity. However, the observed decline in performance under site-wise cross-validation highlights the need to address site-related variability to enhance reproducibility and generalizability in neuroimaging-based predictive models of pediatric obesity.

Objective: The Add Health Cognitive Assessment, Physical, and Sensory Function Protocol (Add CAPS) was developed to assess cognitive, physical, and sensory function in early midlife in a nationally representative sample in the United States. Using Add CAPS, we developed two general cognitive performance measures. Methods: The sample included 2,525 participants from Add Health Wave VI who completed an in- home assessment of cognitive performance. Confirmatory factor analysis (CFA) was used to derive two general cognitive performance (GCP) scores: (1) a five-domain score based on originally designed cognitive domains (Add CAPS GCP), and (2) a modified score aligned with the Harmonized Cognitive Assessment Protocol (HCAP) framework (Add CAPS GCP-H). We evaluated model fit using Root Mean Square Error of Approximation (RMSEA), Standardized Root Mean Square Residual (SRMR), and Comparative Fit Index (CFI) and tested factor scores for criterion validity. Results: Both models showed good fit (Add CAPS GCP: RMSEA = 0.025, SRMR = 0.031, CFI = 0.968; Add CAPS GCP-H: RMSEA = 0.027, SRMR = 0.033, CFI = 0.962), indicating that they adequately represent the underlying GCP construct. Discussion: The Add CAPS cognitive battery captures a robust, hierarchical structure of GCP across alternative domain specifications. The derived factor scores provide a valuable method for characterizing a person's cognitive baseline during midlife. Importantly, the Add CAPS GCP-H enhances comparability with the HCAP network, supporting cross-cohort analyses of cognitive aging.

Adiposity in adolescence can have detrimental effects on neural maturation, and is associated with incompletely understood alterations in brain structures and circuits. To address this important knowledge gap, N=3,341 youth from the Adolescent Brain Cognitive Development (ABCD) two-year follow-up cohort (median(IQR) age=12.0(1.1) years; 51.0% females), with structural MRI and resting-state fMRI were studied. Topological properties reflecting network strength, resilience, efficiency and modularity, information transfer, regional feedback costs associated with controllability of network dynamics, and morphometric characteristics were examined as a function of body mass index (BMI), body roundness index (BRI), overweight, obesity, and persistent excess BMI (across assessments). Youth who slept less, spent more time on electronic devices, were Hispanic and/or from lower-income families had higher BMI/BRI ({beta}=0.07-4.95, 95%CI=[0.03,7.05]), and higher odds of overweight or obesity (aOR=1.01-1.72, 95%CI=[1.01,2.28]). Higher BMI/BRI, overweight, obesity and/or persistent excess BMI were associated with weaker and less resilient networks supporting decision-making, control, emotional regulation, reward processing and social function ({beta}=-0.11 to -0.01, CI=[-0.16, -0.01]), and more topologically fragile thalamus and basal ganglia ({beta}=0.05-0.10, CI=[0.01,0.14], p<0.03). They were also associated with lower control costs in cognitive and topological hubs (including the precuneus and prefrontal regions) that play central roles in regulating brain dynamics, aberrant information transfer in limbic, frontoparietal, salience, somatomotor and cerebellar regions, and lower thickness and/or volume of distributed (including prefrontal) regions, and functional hubs ({beta}=-0.14 to -0.02, CI=[-0.18,-0.01]). Thus, adiposity in adolescence is associated with widespread structural and alterations of brain networks supporting developing cognitive processes, and fundamental mechanisms that control these networks dynamics.